BRAF-mutant metastatic colorectal cancer: Prognostic and predictive value of primary tumor location—A pooled analysis of the AIO studies FIRE-1, CIOX, XELAVIRI, FIRE-3, and VOLFI.
Authors: Annabel Helga Sophie Alig, Volker Heinemann, Sebastian Stintzing, Michael Geissler, Ludwig von Weikersthal, Thomas Decker, Florian Kaiser, Nicolas Moosmann, Kathrin Heinrich, Swantje Held, Julian Walter Holch, Arndt Stahler, Annika Kurreck, Anke C. Reinacher-Schick, Andrea Tannapfel, Frederick Klauschen, Andreas Jung, Clemens Giessen-Jung, Dominik Paul Modest
Journal: Journal of Clinical Oncology (2022)

3576 Background: Primary tumor location (PTL: left vs. right) is an established prognostic marker in metastatic colorectal cancer (mCRC) and has predictive impact for anti-EGFR antibody (mAb) efficacy in patients with RAS ( KRAS and NRAS) wild-type (WT) mCRC. This analysis of five pooled studies evaluates PTL as a prognostic and - concerning anti-EGFR mAb efficacy - predictive marker in BRAF V600E-mutant/ RAS WT and mCRC. Methods: The analysis is based on individual patient data of five pooled 1 st -line studies with varying treatment strategies: the pooled population comprises of BRAF V600E-mutant/ RAS WT ( BRAFmt) mCRC with known PTL. For analysis, treatment was stratified into two groups: treated with or without anti-EGFR mAb. Dichotomous variables (overall response rate, ORR; characteristics) were compared by Chi-Square or Fisher’s exact test and time-to event endpoints (progressive-free survival, PFS; overall survival, OS) by Kaplan-Meier method, log rank test and Cox regression. Results: Of 102 patients (pts) with BRAFmt mCRC, 55 pts (54%) presented with right-sided primary tumors (RPT), 47 (46%) presented with left-sided primary tumors (LPT). Pts with RPT were more likely to be female ( p= 0.04). ORR was inferior in RPT compared to LPT (35% vs. 55%; p= 0.04). No difference was seen in PFS (HR 0.8 (95% CI 0.6-1.3; p= 0.32) or OS (HR 0.8; 95% CI 0.8-1.3; p= 0.46). In male pts PTL trended to be associated with longer OS (HR 0.6; 95% CI 0.3-1.0; p= 0.06). 25 pts with RPT (45%) and 21 with LPT (45%) received anti-EGFR mAb. In pts with LPT anti-EGFR mAb based treatment was associated with higher ORR (81% vs. 35%; p&lt; 0.01). No effect was seen in RPT (ORR 35% vs. 36%; p= 0.82). Anti-EGFR mAb treatment resulted in inferior PFS in RPT (HR 2.0; 95% CI 1.1-3.5; p= 0.02) and showed a trend towards improved PFS in LPT (HR 0.6; 95% CI 0.3-1.1; p= 0.11). Pts with RPT had a worse OS when treated with anti-EGFR mAb (HR 1.8; 95% CI 1.0-3.1; p= 0.05), whereas pts with LPT appeared to have a favorable outcome when treated with an anti-EGFR mAb containing regimen (HR 0.4; 95% CI 0.2-0.7; p&lt; 0.01). Conclusions: This exploratory analysis of five studies suggests that PTL has limited prognostic impact in BRAFmt mCRC but might carry predictive information regarding anti-EGFR mAb efficacy in a 1 st -line treatment setting. Further prospective studies are needed to validate these results and to grasp the differences in the heterogeneous group of BRAFmt pts. Clinical trial information: FIRE-1 was before mandatory registration, NCT00254137, NCT00433927, NCT01249638, NCT01328171.